1lvc

From Proteopedia

Revision as of 14:20, 15 February 2008

Crystal structure of the adenylyl cyclase domain of anthrax edema factor (EF) in complex with calmodulin and 2' deoxy, 3' anthraniloyl ATP

Overview

Edema factor (EF) and CyaA are calmodulin (CaM)-activated adenylyl cyclase, exotoxins involved in the pathogenesis of anthrax and whooping cough, respectively. Using spectroscopic, enzyme kinetic and surface plasmon, resonance spectroscopy analyses, we show that low Ca(2+) concentrations, increase the affinity of CaM for EF and CyaA causing their activation, but, higher Ca(2+) concentrations directly inhibit catalysis. Both events occur, in a physiologically relevant range of Ca(2+) concentrations. Despite the, similarity in Ca(2+) sensitivity, EF and CyaA have substantial differences, in CaM binding and activation. CyaA has 100-fold higher affinity for CaM, than EF. CaM has N- and C-terminal globular domains, each binding two, Ca(2+) ions. CyaA can be fully activated by CaM mutants with one defective, C-terminal Ca(2+)-binding site or by either terminal domain of CaM while, EF cannot. EF consists of a catalytic core and a helical domain, and both, are required for CaM activation of EF. Mutations that decrease the, interaction of the helical domain with the catalytic core create an enzyme, with higher sensitivity to Ca(2+)-CaM activation. However, CyaA is fully, activated by CaM without the domain corresponding to the helical domain of, EF.

Disease

Known diseases associated with this structure: Cavernous malformations of CNS and retina OMIM:[604214], Cerebral cavernous malformations-1 OMIM:[604214], Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations OMIM:[604214], Leukemia, acute T-cell lymphoblastic OMIM:[603025], Leukemia, acute myeloid OMIM:[603025]

About this Structure

1LVC is a Protein complex structure of sequences from Bacillus anthracis and Homo sapiens with , and as ligands. Active as Adenylate cyclase, with EC number 4.6.1.1 Full crystallographic information is available from OCA.

Reference

Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins., Shen Y, Lee YS, Soelaiman S, Bergson P, Lu D, Chen A, Beckingham K, Grabarek Z, Mrksich M, Tang WJ, EMBO J. 2002 Dec 16;21(24):6721-32. PMID:12485993

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